Bisphenol A (BPA) is used in the manufacture of polycarbonate plastics and epoxy resins which are used in food containers and medical devices, as well as for multiple products in the automotive and computer industries. BPA is a high volume chemical worldwide; the US produced 2.3 billion tons in 2004. At high exposure levels, BPA is unequivocally associated with reproductive and developmental toxicity; whereas adverse effects at lower levels are controversial. Only free (nonconjugated) BPA is believed to be toxic. In adults, BPA is predominantly conjugated with glucuronide; the predominant human enzyme responsible is UGT2B15. This enzyme is known to exhibit a common, functional polymorphism, but its impact on human BPA metabolism is unknown. Human BPA sulfation also has been reported, but its relative importance is unclear. Adult humans conjugate BPA well with only about 10% of individuals exhibiting measurable free urinary BPA. Whether infants and young children conjugate BPA sufficiently to avoid toxicity has been debated extensively in the absence of data. In a controversial neonatal mouse study, BPA conjugation was so limited that the first pass metabolism effect was lost, resulting in similar blood concentrations after oral and IV dosing. If similar circumstances occur in immature humans, many argue that multiple studies showing toxicity after relatively low subcutaneous dosing are relevant. In spite of an extensive BPA literature, no accurate human infant biomonitoring data or data defining the human ontogeny of BPA disposition are available. Thus, the overall goal of this application is to fill critical data gaps to allow improved scientific BPA risk assessment. The specific aims are: 1) To determine the impact of prematurity on in vivo human BPA conjugation ability by determining urinary BPA and its conjugates in a cross sectional cohort of newborns using a stratified recruitment strategy powered to test the impact of gestational age from 24 to 40 weeks. In addition, in a longitudinal subset of this cohort, we will determine the impact of postnatal age on urinary free BPA concentrations over the first six months of life; 2) To determine the impact of a common, functional UGT2B15 genetic polymorphism on BPA glucuronidation; and 3) To characterize both in vitro human UGT2B15 ontogeny and the developmental changes in BPA metabolism in a large, well-characterized bank of human liver microsomes from donors ranging in age from 8 weeks gestation to 18 years postnatal age. For all three aims, we will use a high quality, sensitive HPLC tandem mass spectrometric assay to determine total, conjugated, and free urinary BPA. We also will explore the question of BPA sulfation in infants, as well as gather relevant data to explore putative BPA sources, including medical devices, in both infants and their mothers. Without the results of this study, the vast number of BPA animal studies will remain controversial and of limited risk assessment use. Irrespective of the outcome of the proposed hypotheses testing, the data generated will have significant public health impact and will be used for risk assessment for this high volume, ubiquitous chemical. PUBLIC HEALTH RELEVANCE: The proposed work will fill the following data gaps limiting human bisphenol A (BPA) risk assessment: 1) quantification of human newborn BPA exposure and the impact of prematurity and postnatal age on BPA metabolism; 2) determination of whether a common, functional genetic difference in UGT2B15 (the enzyme that metabolizes BPA) is associated with differences in BPA disposition; and 3) characterization of the developmental pattern of UGT2B15 such that physiologic mathematical modeling of BPA A disposition across development can be achieved. Without the results of this study, the vast number of BPA animal studies will remain controversial and of limited risk assessment use. Irrespective of the outcome of the proposed hypotheses testing, the data generated will have significant public health impact and will be used for risk assessment for this high volume, ubiquitous chemical.